Central 5-HT 1 and 5-HT 2 binding sites in transgenic mice with reduced glucocorticoid receptor number

Abstract

Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA, which partially blocks glucocorticoid receptor expression, were used in order to clarify the role of glucocorticoid receptors in the regulation of 5-HT 1A, 5-HT 1nonA and 5-HT 2 binding sites labelled by quantitative autoradiography in the frontal and prefrontal cortex, striatum, hypothalamus, amygdala and raphe nuclei. We found that 1 nM [ 3H]8-hydroxy-2-[di- N-propylamino]tetralin ([ 3H]8-OH-DPAT) binding to 5-HT 1A sites was decreased in strata oriens (−15.1±3.5%) and radiatum–lacunosum–moleculare (−13.3±4.3%) of the hippocampal CA 3 area, and 2 nM [ 3H]5-hydroxytryptamine binding to 5-HT 1nonA sites in the presence of 100 nM 8-OH-DPAT and mesulergine was decreased in the dorsal subiculum (−17.8±6.9%). By contrast, 5-HT 2 sites labelled by 0.5 nM of (±)-1-(2,5-dimethoxy-4-[ 125I]iodophenyl)-2-aminopropane was increased in the dorsal subiculum (+35.2±11.5%) and CA 2 area (+29.2±11.3%). The observed differences in binding to 5-HT 1 and 5-HT 2 sites were all located in areas of the hippocampus that contain both gluco- and mineralo-corticoid receptors, and no difference was observed in anatomical structures which contain only glucocorticoid receptors. Therefore, it seems that the important factor for the regulation of these 5-HT receptors is the interaction between gluco- and mineralo-corticoid receptors rather than the absolute density of glucocorticoid receptors. These results suggest that some of the alterations of the serotonergic neurotransmission observed in depressed patients might be secondary to an altered glucocorticoid receptor function.